This application is the national phase under 35 U.S.C. xc2xa7 371 of PCT International Application No. PCT/HU98/00027 which has an International filing date of Mar. 20, 1998, which designated the United States of America.
The invention relates to antitussive formulations containing theobromine [3,7-dihydro-3,7-dimethyl-1H-purine-2,6-dione] of the formula (III) or its salts or its complexes as antitussive agent.
It is known that the three natural methylxantine alkaloids, namely theophylline of the formula (I), caffeine of the formula (II) and theobromine of the formula (III) are found in the leaves of tea (Thea sinensis), cacao-seed (Theobroma cacao) and coffee-berry (Coffea arabica). These plants have high relevance in human alimentation because they are the source of several widely-consumed goods and beverages.
In tea besides theophylline and theobromine the caffeine is the main alkaloid. In coffee the caffeine is the dominant alkaloid while in cocoa powder and in chocolate-liquor which is the basic material for chocolate, theobromine is the main alkaloid but it also contains some caffeine.
The three natural methylxanthines (I, II, III) have complex biological effects but despite of the close chemical similarity there are significant differences with respect to the strength of efficacy and in the spectrum of their effects.
It is generally accepted in the literature that the wide-spectrum of the pharmacological effects of methylxanthines can be deduced from two main molecular mechanisms. One is the non-specific inhibition of the cyclic nucleotide phosphodiesterases (PDEs) and the second is the antagonism of adenosine receptors. Numerous alkylxanthines have been examined and it is established, as a general rule, that both mentioned effects decrease if there is no substituent on the N1 atom of the xanthine moiety or if the N7 atom contains a substituent, as compared with the corresponding 1,3-dialkylxanthine.
In the case of theobromine the N1 atom is not but the N7 atom is substituted so according to the general rule the activity of the theobromine should be weaker than either that of caffeine or theophylline. Really, the activity rank order of the three naturally occurring methylxanthines in respect of the PDE inhibition and the adenosine antagonism is the following: theophylline greater than caffeine greater than theobromine.
It is a very important and a clinically highly relevant feature of the methylxanthines, especially of theophylline, that they relax the different types of smooth muscles both in vivo and in vitro. The bronchial smooth muscle relaxant effect and other excellent therapeutic properties of theophylline are widely used for the treatment of asthma. The similar effects of theobromine and caffeine are much less pronounced than those of theophylline.
It is known and supported by the high popularity of the consumption of tea and caffeine containing beverages that both caffeine and theophylline have strong central nervous system (CNS) stimulating effects. The effect of theobromine on the CNS is weaker than either that of caffeine or theophylline (Mumford, G. K. et al., Psychopharmacology, 1994, 115:1).
Both caffeine and theophylline have strong and complex effects on cardiac muscle and the cardiovascular system, It is known that these compounds have remarkable peripheral vascular dilating effects, but at higher doses they also cause tachycardia. Theobromine has much weaker cardiovascular effects.
The diuretic effect is a very characteristic feature of these methylxantines (I, II, III), especially of theophylline. Theobromine has only a weak diuretic effect compared either to theophylline or caffeine.
The differences, which exist in the useful therapeutic effects of the natural methylxanthines, can be found in their side and toxic effects, too. Due to the narrow therapeutic dose-range of theophylline the risk of the overdosing is high, while it is weaker in the case of caffeine. The risk of dangerous side effects caused by theobromine is negligible compared to either theophylline or caffeine (Stavric, B., Fd.Chem.Toxic. 1988, 26:725).
The scientific literature dealing with naturally occurring methylxanthines especially with theophylline and caffeine is extraordinarily broad. Data can be found in some thousands of scientific papers, patent specifications, reviews and books concerning this topic. These studies suggest that due to the poor biological activity of theobromine, the compound has no therapeutic relevance. The above opinion is supported by one of the most well known pharmacological book:
xe2x80x9cTheophylline, caffeine, and theobromine share in common several pharmacological actions of therapeutic interest. They relax smooth muscle, notably bronchial muscle, stimulate the central nervous system (CNS), stimulate cardiac muscle, and act on the kidney to produce diuresis. Since theobromine displays a low potency in these pharmacological actions, it has all but disappeared from the therapeutic scene. xe2x80x9d(Rall, T. V., In: Goodman and Gilman""s, The Pharmacological Basis of Therapeutics, 8th Ed., p. 620, Pergamon Press, New York, 1990). No reference has been found to the antitussive effect of theobromine.